Mechanisms of urban change: Regeneration companies or development corporations?

This article is an early assessment of the role and performance of URCs, benchmarked against the UDC model. It identified weaknesses and vulnerability of URCs in relation to control over land

CD4+ T-cell responses to Epstein-Barr virus nuclear antigen EBNA1 in Chinese populations are highly focused on novel C-terminal domain-derived epitopes

Epstein-Barr virus nuclear antigen EBNA1, the one viral protein uniformly expressed in nasopharyngeal carcinoma (NPC), represents a prime target for T-cell-based immunotherapy. However, little is known about the EBNA1 epitopes, particularly CD4 epitopes, presented by HLA alleles in Chinese people, the group at highest risk for NPC. We analyzed the CD4$^+$ T-cell responses to EBNA1 in 78 healthy Chinese donors and found marked focusing on a small number of epitopes in the EBNA1 C-terminal region, including a DP5- restricted epitope that was recognized by almost half of the donors tested and elicited responses able to recognize EBNA1-expressing, DP5-positive target cells

CD4+ T-cell responses to Epstein-Barr virus (EBV) latent-cycle antigens and the recognition of EBV-transformed lymphoblastoid cell lines

There is considerable interest in the potential of Epstein-Barr virus (EBV) latent antigen-specific CD4$^+$ T cells to act as direct effectors controlling EBV-induced B lymphoproliferations. Such activity would require direct CD4$^+$ T-cell recognition of latently infected cells through epitopes derived from endogenously expressed viral proteins and presented on the target cell surface in association with HLA class II molecules. It is therefore important to know how often these conditions are met. Here we provide CD4$^+$ epitope maps for four EBV nuclear antigens, EBNA1, -2, -3A, and -3C, and establish CD4$^+$ T-cell clones against 12 representative epitopes. For each epitope we identify the relevant HLA class II restricting allele and determine the efficiency with which epitope-specific effectors recognize the autologous EBV-transformed B-lymphoblastoid cell line (LCL). The level of recognition measured by gamma interferon release was consistent among clones to the same epitope but varied between epitopes, with values ranging from 0 to 35% of the maximum seen against the epitope peptide-loaded LCL. These epitope-specific differences, also apparent in short-term cytotoxicity and longer-term outgrowth assays on LCL targets, did not relate to the identity of the source antigen and could not be explained by the different functional avidities of the CD4$^+$ clones; rather, they appeared to reflect different levels of epitope display at the LCL surface. Thus, while CD4$^+$ T-cell responses are detectable against many epitopes in EBV latent proteins, only a minority of these responses are likely to have therapeutic potential as effectors directly recognizing latently infected target cells

Combined assessment (aspiration cytology and mammography) of clinically suspicious breast masses

We examined the safety and utility of the combined assessment of aspiration cytology and mammography in 705 women who had clinically suspicious or malignant palpable breast masses. Histological assessment confirmed 176 benign and 529 malignant lesions. There were no incorrect (false positive) diagnoses made in the 176 benign masses when combined assessment was used (specificity 1,0; predictive value 0,86); in isolation, however, there was a false positive cytological diagnosis («papillary carcinoma») and 3 false positive mammographic diagnoses. Benign disease (false negative) was incorrectly diagnosed by combined assessment in 4 of the 529 malignant masses (sensitivity 0,99; predictive value 0,98): cytological diagnoses were of fat necrosis (2) and benign cells on cytospin (1) and aspiration biopsy (1); mammographic diagnoses were of benign disease (2) and normality (2). Indeterminate («atypical», «suspicious») diagnoses were problematic and frequent (overall 223 (31,6%), malignant masses 137 (25,9%), benign masses 86 (48,9%); cytology 117 (16,6%), mammography 141 (20%). Thus, with the combined assessment of mammography and cytology in clinically suspicious breast masses, a decisive diagnosis was made in about two-thirds of cases allowing the safe commencement of therapy; the balance of patients required cone or excision biopsy

Combined assessment (aspiration cytology and mammography) of clinically suspicious breast masses

We examined the safety and utility of the combined assessment of aspiration cytology and mammography in 705 women who had clinically suspicious or malignant palpable breast masses. Histological assessment confirmed 176 benign and 529 malignant lesions. There were no incorrect (false positive) diagnoses made in the 176 benign masses when combined assessment was used (specificity 1,0; predictive value 0,86); in isolation, however, there was a false positive cytological diagnosis ('papillary carcinoma') and 3 false positive mammographic diagnoses. Benign disease (false negative) was incorrectly diagnosed by combined assessment in 4 of the 529 malignant masses (sensitivity 0,99; predictive value 0,98): cytological diagnoses were of fat necrosis (2) and benign cells on cytospin (1) and aspiration biopsy (1); mammographic diagnoses were of benign disease (2) and normality (2). Indeterminate ('atypical', 'suspicious') diagnoses were problematic and frequent (overall 223 (31,6%), malignant masses 137 (25,9%), benign masses 86 (48,9%); cytology 117 (16,6%), mammography 141 (20%). Thus, with the combined assessment of mammography and cytology in clinically suspicious breast masses, a decisive diagnosis was made in about two-thirds of cases allowing the safe commencement of therapy; the balance of patients required core or excision biopsy

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity

Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes

Background: Patients with multiple sclerosis (MS) have a decreased frequency of CD8(+) T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. We have proposed that this might predispose to the development of MS by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. The decreased CD8(+) T cell response to EBV results from a general CD8(+) T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8(+) T cell population. Because decreased HLA class I expression on monocytes and B cells has been reported in MS and could influence the generation and effector function of EBV-specific CD8(+) T cells, the present study was undertaken to measure the expression of HLA molecules on B cells and monocytes in patients with MS

Conditional Immortalization of Human B Cells by CD40 Ligation

It is generally assumed that human differentiated cells have a limited life-span and proliferation capacity in vivo, and that genetic modifications are a prerequisite for their immortalization in vitro. Here we readdress this issue, studying the long-term proliferation potential of human B cells. It was shown earlier that human B cells from peripheral blood of healthy donors can be efficiently induced to proliferate for up to ten weeks in vitro by stimulating their receptor CD40 in the presence of interleukin-4. When we applied the same stimuli under conditions of modified cell number and culture size, we were surprised to find that our treatment induced B cells to proliferate throughout an observation period of presently up to 1650 days, representing more than 370 population doublings, which suggested that these B cells were immortalized in vitro. Long-term CD40-stimulated B cell cultures could be established from most healthy adult human donors. These B cells had a constant phenotype, were free from Epstein-Barr virus, and remained dependent on CD40 ligation. They had constitutive telomerase activity and stabilized telomere length. Moreover, they were susceptible to activation by Toll-like receptor 9 ligands, and could be used to expand antigen-specific cytotoxic T cells in vitro. Our results indicate that human somatic cells can evade senescence and be conditionally immortalized by external stimulation only, without a requirement for genetic manipulation or oncoviral infection. Conditionally immortalized human B cells are a new tool for immunotherapy and studies of B cell oncogenesis, activation, and function

How is genetic testing evaluated? A systematic review of the literature

open8Given the rapid development of genetic tests, an assessment of their benefits, risks, and limitations is crucial for public health practice. We performed a systematic review aimed at identifying and comparing the existing evaluation frameworks for genetic tests. We searched PUBMED, SCOPUS, ISI Web of Knowledge, Google Scholar, Google, and gray literature sources for any documents describing such frameworks. We identified 29 evaluation frameworks published between 2000 and 2017, mostly based on the ACCE Framework (n = 13 models), or on the HTA process (n = 6), or both (n = 2). Others refer to the Wilson and Jungner screening criteria (n = 3) or to a mixture of different criteria (n = 5). Due to the widespread use of the ACCE Framework, the most frequently used evaluation criteria are analytic and clinical validity, clinical utility and ethical, legal and social implications. Less attention is given to the context of implementation. An economic dimension is always considered, but not in great detail. Consideration of delivery models, organizational aspects, and consumer viewpoint is often lacking. A deeper analysis of such context-related evaluation dimensions may strengthen a comprehensive evaluation of genetic tests and support the decision-making process.openPitini, Erica*; de Vito, Corrado; Marzuillo, Carolina; D’Andrea, Elvira; Rosso, Annalisa; Federici, Antonio; Di Maria, Emilio; Villari, PaoloPitini, Erica; de Vito, Corrado; Marzuillo, Carolina; D’Andrea, Elvira; Rosso, Annalisa; Federici, Antonio; Di Maria, Emilio; Villari, Paol